Process for preparing p-amino phenols by electrolysis

ABSTRACT

p-Amino phenols of the formula ##STR1## wherein R 1  nd R 2  are independently hydrogen, optionally substituted alkyl, halogen, COOH, SO 3  H or NO 2 , are produced by electrolytic reduction of p-phenylazophenols of the formula ##STR2## wherein R 1  and R 2  are as defined above, in an aqueous basic medium at a pH value at least equal to the pKa value of the p-phenylazophenol and at a temperature of at least 50° C., preferably 70° to 100° C. 
     The compounds (I) can hereby be produced without problems, in particular of an environmental nature, which are associated with the chemical reducing methods. 
     The process is particularly useful for the preparation of the compound 5-aminosalicylic acid which is a valuable active component of certain medicaments for the treatment of colitis ulcerose and Crohn&#39;s disease.

The present invention concerns a process for the preparation of p-aminophenols of the general formula I set forth in the introductory protionof claim 1, by electrolytic reduction of p-phenylazophenols in anaqueous medium, and the process of the invention is characterized byperforming the electrolytic reduction in a basic medium at a pH value atleast equal to the pKa value of the p-phenylazophenol and at an elevatedtemperature of at least 50° C. and preferably about 70° to 100° C. Inthis process, e.g. the compound 5-aminosalicylic acid may beconveniently obtained, said compound being a valuable active componentin certain medicaments, cf. the PCT Application No. 81/02671, for thetreatment of colitis ulcerose and Crohn's disease.

Arylazophenols of the general formula

    Ar--N═N--Ar'--OH

wherein Ar and Ar' are optionally substituted phenyl groups, can beproduced by coupling a diazoted aromatic amine (an arylidiazoniumcompound) with a phenol in a basic medium (H. E. Fierz-David & L.Blangley: Grundlegende Operationen der Farbenchemie, 5th ed., Vienna1943). This known coupling reaction has been used for many years in theproduction of dyes. The reaction is as follows:

    ArNH.sub.2 +[NO.sup.+ ]→ArN.sup.+ .tbd.N+H.sub.2 O  (1)

    ArN.sup.+ .tbd.N+Ar'OH+2OH.sup.- →Ar--N═N--Ar'O.sup.- +H.sub.2 O (2)

Arylazophenols can be reduced electrolytically in an acid medium toamines and amino phenols. The reaction can either take place directly(see e.g. Chem. Abstr., 13, 843 (1919) and Chem. Abstr., 15, 839 (1921))or indirectly (see J. F. Norris & F. O. Cummings, Ind. Eng. Chem., 17,305 (1925) and the U.S. Pat. No. 1,542,265). However, such a reaction isdifficult to carry out with a good yield in practice since thearylazophenol is sparingly soluble in an aqueous acid, unless itcontains an HSO₃ group or an NR₂ group in which the two R groups are thesame or different and represent hydrogen or alkyl. It has been attemptedto use an alcoholic hydrochloric acid solution (E. Puxeddu, Gazz. Chim.Ital. 48 (II), 25 (1919)), and it has been proposed to add organicsolvents, providing for some, but frequently not sufficient improvementin solubility. Moreover, purification and recovery of the solvent poseproblems.

Also the U.S. Pat. No. 3,645,864 describes electrolytic reduction in anacid medium. In this case, the starting material is nitrobenzene whichis reduced to p-amino phenol and its derivatives at 60° to 150° C. andat a cathode potential of -0.25 to -0.35 V with respect to a saturatedcalomel electrode.

According to the DE Offenlegungsschrift No. 2 256 003, electrolyticpreparation of amino phenols proceeds in a basic medium, the electrolytesolution being an alkali metal hydroxide solution. However, the startingmaterials are nitrosophenols which must be synthesized beforehand in aninert atmosphere, and to obtain reasonable results it is necessary touse a large number of electrolysis cells in series connection.

In view of polarographic studies (see T. M. Florence, Austr. J. Chem.,18, 609 (1965); T. M. Florence, J. Electroanal. Chem., 52, 115 (1974);H. A. Laitinen & T. J. Kneip, J. Am. Chem. Soc., 78, 736 (1956) andChem. Abstr. 48, 4333 (1954) the following mechanism has been proposedfor the reductive cleavage of p-arylazophenols (here shown withp-phenylzophenol): ##STR3##

It will be seen that the reaction outlined above involves a total of 4electrons (n=4). The slow step in the reaction sequence is step (4), andthe polarographic results show in fact that the reaction (4) proceeds soslowly in a basic liquid that it cannot be observed at all under suchcircumstances. Thus, the final step (5) is not observed either, and, inpractice, only n=2 is obtained by polarography in a sufficiently basicliquid, for a number of compounds already at pH values of 5.0 andhigher. Accordingly, Puxeddu (Gazz. Chim. Ital. 50 (II), 149 (1920))found no p-amino phenol by reduction of hydroxyazobenzene in a basicliquid.

Some heterocyclic compounds, e.g. 4-pyridylazophenol, can be cleaved byelectrolytic reduction in a basic liquid (T. M. Florence, J.Electroanal. Chem., 52, 115 (1974)), the mechanism being presumably asfollows (and not as shown on p. 124 in the reference): ##STR4## followedby reaction (5) above. Cleavage (7) proceeds reasonably rapidly becausePyNH⁻ (compared to C₆ H₅ NH⁻) is a considerably weaker base. The reasonis that the pyridine ring has strong electron attraction so the negativecharge is less concentrated on the amine nitrogen. Other stronglyelectron attracting groups will act in the same manner.

It has now surprisingly been found that it is possible to reducep-arylazophenols electrolytically at relatively high pH values (pH≧thepKa value of the p-arylazophenol) and suitably high temperatures(preferably of the order of 50° to 100° C.), resulting in an amine and ap-amino phenol. The advantage of using pH values higher than or equal tothe pKa values is in particular that the p-arylazophenols are soluble inaqueous media under these circumstances.

Previously, p-arylazophenols were reduced in basic media by chemicalmethods, e.g. with Na₂ S or Na₂ S₂ O₄, see the U.S. Pat. No. 1,882,758.However, the use of chemical reducing agents generally causeenvironmental problems because e.g. 4 moles of SO₂ per mole of productare formed by the use of Na₂ S₂ O₄, and problems may also be attached tothe purification. In the electrolytic reduction, in contrast, the"reagent" is electrons which do not give rise to problems of theabove-mentioned type. Another point in this connection is the economicaspects since the prices of electricity have risen less than the pricesof chemicals in recent years.

The present process can in principle be used for the reduction of allarylazophenols with the single restriction that the phenol group ispara-positioned with respect to the azo group. The two substituents R₁and R₂ are independently selected from among hydrogen, optionallysubstituted alkyl groups, halogens, COOH, SO₃ H or NO₂ ; the type of thesubstituents is not critical when only the substituents are not reducedunder the given reaction conditions.

The electrolysis is performed in an aqueous basic medium whose pH valueis determined by the pKa of the p-arylazophenol used as the startingmaterial. In practice, pH will be 8 to 10 or more, depending upon thestarting material. It is believed that the reaction rate increases withincreasing pH, so pH>12 is often used. The temprature used issufficiently high to ensure a reasonable reaction rate. Frequently, thistemperature is between 70° and 100° C., at which the reduction proceedsat a reasonably high rate. Temperatures above 100° C. can also be used,but this is no advantage in terms of energy.

Lower temperatures, more particularly down to 50° C., may also be used,but in such cases it is necessary to use lower current densitites, andeven though the reaction also proceeds e.g. at room temperature, thereaction rate is so slow that it is not attractive in practice to workat this temperature.

The potential used is up to 0.7 V, preferably about 0.5 V more negativethan the reduction potential (halfwave potential) at the given pH value.A more negative potential is not harmful, unless other groups orsubstances are reduced by this. The potential is not significantlytemperature-sensitive. The current intensity used is the current density(A/dm²) multiplied by the electrode area. The current density useddepends upon the supply of reducible material, which is a function ofconcentration and transport conditions (laminar or turbulent flow) inthe reactor.

Preferred compounds produced by the process of the invention are p-aminophenol and 5-aminosalicylic acid.

The invention will be illustrated more fully by the following examples.

EXAMPLE 1 Preparation of 5-aminosalicylic acid A. Preparation of5-phenolazosalicylic acid

18.6 kg (200 moles) of aniline are dissolved in a mixture of 40 litersof concentrated hydrochloric acid and 45 liters of water with stirringin a container (A). Cooling is effected to 0° C., and a solution of 14kg of sodium nitrite in 40 liters of water from another container (B) isslowly added with good stirring, so that the temperature does not exceed2° C. After completed addition, stirring continues for another 15minutes, and then about 4 kg of anhydrous sodium carbonate are added inminor portions with stirring. Then pH is between 1 and 2.

In a third container (C), 28 kg (202 moles) of salicylic acid aredissolved in 33 liters of concentrated sodium hydroxide solution (500 gof NaOH in 1 liter solution) and 67 liters of water to which 2 kg ofanhydrous sodium carbonate have been added. After cooling to 0° C., thecontents are pumped slowly from the container (A) and with stirring to acontainer (C), so that the temperature is kept below 5° C. The azocompound gradually precipitates and finally becomes a thickporridge-like mass. The last part of the coupling proceeds slowly, andit is necessary to stir for 5 or 6 hours after completed addition of thediazo solution from the container (A).

B. Reduction of 5-phenylazosalicylic acid

20 liters of a concentrated sodium hydroxide solution (500 g of NaOH in1 liter solution) are added to the contents in the container (C), andheating is performed until everything has been dissolved and pH is above12. Then the contents are pumped into another container (D), followed byheating to 80° C. The contents are pumped through the electrolysis cell,which may be a "filter press cell" (SU Electro Syn Celle) with a leadcathode potential of at least -1.4 V (measured against a standardcalomel electrode). The current density is 10 to 20 A/dm². After 2,000Ah, the current density is reduced to 2 to 3 A/dm², and after another 2hours the electrolysis is stopped. The solution is decolored by additionof 5 kg of sodium hydrosulfite and is pumped into a container (F) blownthrough with nitrogen.

40 kg of NaOH are dissolved in 250 liters of water in a container (E),and the solution is used as anode liquid. It is important for the lifeof the anodes that the solution is always strongly basic.

Water steam (optionally superheated steam) is conveyed to the contentsin the container (F), and the resulting aniline is distilled off withwater steam. Then concentrated hydrochloric acid is added to a pH of4.1, and cooling is effected to 0° to 5° C. with stirring. After acouple of hours the crystallization has terminated, and the resulting5-aminosalicylic acid is isolated by centrifugation or in a filterpress. Yield: Approximately 28 kg of a sligtly coloured substance whichis purified by recrystallization from water followed by decolorationwith active carbon.

EXAMPLES 2-7

The electrolytic preparation of 5-aminosalicylic acid is examined undervarious conditions in these examples. 0.4 mole of 5-phenylazosalicylicacid is used for each electrolysis and is prepared as follows:

74.5 g of redistilled aniline are dissolved with stirring in a mixtureof 160 ml of concentrated hydrochloric acid and 180 ml of demineralizedwater, and cooling is effected to 0° C. in an ice/salt bath. 56 g ofNaNO₂ dissolved in 160 ml of demineralized water and cooled to 0° C. areslowly added with stirring to the aniline hydrochloride solution, sothat the temperature does not exceed 2° C. After completed addition thepH is 1.0 to 1.5.

112 g of salicylic acid are dissolved with stirring in a mixture of 132ml of concentrated NaOH (500 g in 1 liter solution) and 268 ml of H₂ O.

After cooling to 0° C., the diazo compound is added slowly and withstirring, so that the temperature does not exceed 5° C. The resultingcoupling product is a viscous mass which is stirred overnight.

The resulting azo compound (0.8 mole) is admixed with a mixture ofconcentrated NaOH and water to dissolve the coupling product before theelectrolysis. The pH value hereby exceeds 12. The produced amount of azocompound is sufficient for two electrolyses.

Half of the solution (corresponding to 0.4 mole of 5-phenylazosalicylicacid) is poured into the cathode compartment of the electrolysis cell.An NaOH solution is poured into the anode compartment. The contents arepumped through the electrolysis cell, and the reaction is started. Whenthe electrolysis has terminated, the reduction product is tapped into aflask. Cooling is effected, and HCl is added to pH 4.0. After filtrationthe residue (5-aminosalicylic acid) is washed in H₂ O and acetone.

The electrolysis is performed in a conventional electrolysis cell inwhich the anode compartment and the cathode compartment are separated bya semi-permeable membrane. The cathode is of lead, and the anode is ofnickle. The cathode reference electrode is an Ag/AgCl electrode.

The reference voltage must be greater than 0.8 V, which is the naturalpotential of the Ag/AgCl electrode. A reference voltage below this valuemeans that there will be no reduction. The reference voltage should beas close to 1.5 V as possible and be maintained at that value in orderfo the reduction to proceed satisfactorily.

The electrolysis conditions used are set forth in the following table.Also the yield of crude 5-aminosalicylic acid obtained by eachelectrolysis appears from the table.

    __________________________________________________________________________       Addition to                                                                   0.8 mole                 Voltage                                                                            Reference  Total Yield                       Ex.                                                                              coupling Electrolysis                                                                         Anode                                                                              Mem-                                                                              anode                                                                              voltage                                                                             Current                                                                            Electrolysis                                                                        Crude product               No.                                                                              compound temperature                                                                          liquid                                                                             brane                                                                             cathode                                                                            cathode                                                                             intensity                                                                          current                                                                             (% of                       __________________________________________________________________________                                                      theory)                     2  2 moles NaOH                                                                           60° C.                                                                        8 moles                                                                            a   constant                                                                           app. 1.2 V                                                                          3-4 A                                                                              48 Ah 86                             in              NaOH in  6 V                                                  200 ml H.sub.2 O                                                                              2 l H.sub.2 O                                              3  2 moles NaOH                                                                           70° C.                                                                        8 moles                                                                            a   constant                                                                           1.2-1.3 V                                                                           5 A  59 Ah 85                             in              NaOH in  6 V                                                  200 ml H.sub.2 O                                                                              2 l H.sub.2 O                                              4  2 moles NaOH                                                                           70° C.                                                                        8 moles                                                                            b   constant                                                                           1.3-1.45 V                                                                          8.7 A                                                                              52 Ah 79                             in              NaOH in  6 V                                                  200 ml H.sub.2 O                                                                              2 l H.sub.2 O                                              5  1 mole NaOH                                                                            70° C.                                                                        8 moles                                                                            b   constant                                                                           1.25-1.4 V                                                                          8A   47 Ah 75                             in              NaOH in  6 V                                                  200 ml H.sub.2 O                                                                              2 l H.sub.2 O                                              6  2 moles NaOH                                                                           70° C.                                                                        8 moles                                                                            c   constant                                                                           1.4-1.6 V                                                                           7.8 A                                                                              47 Ah 75                             in              NaOH in  6 V                                                  200 ml H.sub.2 O                                                                              2 l H.sub.2 O                                              7  1.5 moles NaOH                                                                         80° C.                                                                        8 moles                                                                            d   constant                                                                           1.3-1.5 V                                                                           7.0 A                                                                              60 Ah 72                             in              NaOH in  6 V                                                  200 ml H.sub.2 O                                                                              1 l H.sub.2 O                                              __________________________________________________________________________     a "mc" 3470 from Sybron Chemical                                              b "Nafion ®" 324                                                          c "Nafion ®" 423                                                          d a "Nafion ®" membrane.                                             

In example 2, owing to the relatively low temperature of 60° C., thereference voltage has only just reached 1.2 V (however not all thetime). This involves an inferior reaction process, and the reactionshould therefore proceed at a temperature of at least 70° C. The highyield of production in example 2 is probably due to the relatively greatunreliability associated with the test because the substance quantitiesinvolved are very small.

EXAMPLE 8 Preparation of p-amino phenol

In an H-cell (see H. Lund; "Practical Problems in Electrolysis" in"Organic Electrochemistry", 2nd ed., edited by M. M. Baizer and H. Lund,Marcel Dekker, New York 1983, p. 168) consisting of two 250 ml conicalflasks connected through a semi-permeable membrane ("Nafion"®) andequipped with a mercury cathode and a carbon anode, the cathodecompartment is filled with a solution of 10 g of p-hydroxyazobenzene in150 ml 0.2M sodium hydroxide, with pH exceeding 12, and the anodecompartment is filled with 0.5M sodium hydroxide. The cathodecompartment is provided with a thermometer and a reflux condenser.Venting with nitrogen, and a nitrogen atmosphere is maintained in thecathode compartment during the entire reduction. The temperature isincreased to 80° C., and electrolysis is performed at -1.2 V, measuredagainst a standard calomel electrode, with stirring with a magnetstirrer. The initial current density is about 10 A/dm². This graduallydecreases, and the solution changes from being opaque to be justslightly coloured (pale brown). The reflux condenser is replaced by adistillation device, and most of the resulting aniline is distilled off,the temperature being increased to about 100° C. The flow of nitrogenand water steam transfers the aniline into the collecting flask.

The cathode liquid is cooled and neutralized to ph about 6.5. Afterstanding at 0° C., 4.6 g (84%) of p-amino phenol are filtered off asslightly pale brown crystals.

EXAMPLE 9 Preparation of 2-chloro-3-amino phenol

10 g of 4-phenylazo-2-chlorophenol are reduced in the same manner as inexample 8. The yield is 5.4 g (86%) of 2-chloro-4-amino phenol with amelting point of 153° C.

I claim:
 1. A process for preparing p-amino phenols of the generalformula ##STR5## wherein R₁ and R₂ are independently hydrogen,optionally substituted alkyl, halogen, COOH, SO₃ H or NO₂, byelectrolytic reduction of p-phenylazophenols of the formula ##STR6##wherein R₁ and R₂ are as defined above, in an aqueous medium,characterized by performing the electrolysis in a basic medium at a pHvalue at least equal to the pKa value of the p-phenylazophenol and at anelevated temperature of at least 50° C., preferably about 70° to 100° C.2. A process according to claim 1, characterized in that the resultingcompound is 5-aminosalicylic acid.
 3. A process according to claim 1,characterized in that the resulting compound is p-amino phenol.
 4. Aprocess according to claim 1, characterized in that the resultingcompound is 2-chloro-4-amino phenol.
 5. A process according to claim 1,characterized in that pH exceeds
 12. 6. A process according to claim 1,characterized in that the potential is between 0.1 and 0.7 V morenegative than the halfwave potential of the compound which is beingreduced, at the pH value used.